ATP13A2-Mediated Spermine Export Modulates Lipid Catabolism in the Endolysosomal System of SH-SY5Y Cells

Abstract

Dysfunction of the membrane transporter P5B-ATPase 13A2 (ATP13A2) has been linked toneurodegenerative disorders, while its overexpression has been associated with colorectalcancer. ATP13A2 localizes to lysosomes and late endosomes, where it exports polyaminessuch as spermine into the cytosol. We previously showed that ATP13A2 expression alterslipid homeostasis and reduces the levels of bis(monoacylglycero)phosphate (BMP), ananionic phospholipid essential for lipid digestion in acidic compartments, suggesting thatATP13A2-mediated spermine export may affect lysosomal lipid catabolism. α/β-hydrolasedomain-containing 6 (ABHD6), the enzyme responsible for BMP catabolism, was detectedby immunofluorescence and immunoblot analysis in SH-SY5Y cells overexpressing humanATP13A2 and treated with spermine. The activities of the lipid-degrading hydrolasesacid ceramidase (ACase) and glucocerebrosidase (GCase) were measured using specificfluorogenic substrates. ATP13A2-expressing cells showed higher ABHD6 expression,and spermine treatment promoted its translocation to the cytoplasm. Spermine induceda transient increase in ACase activity, followed by a stronger inhibition in ATP13A2-expressing cells. Moreover, GCase activity was elevated in these cells but also showedgreater spermine-induced inhibition. Altogether, these results suggest that ATP13A2-mediated spermine export modulates the lipid digestion capacity of the endolysosomalsystem and support a functional interplay between polyamine and lipid metabolism inthese organelles.